Resistance to viral leukemogenesis in mice is markedly influenced by several categories of genes of the host. One of these is the major histocompatibility locus, H-2, a small but complex region of chromosome 17 within which at least two different loci appear to influence the course of the disease, probably by two different mechanisms. This proposal addresses itself to the problem of elucidating these mechanisms. Although several hypotheses are available to explain the H-2 effect on viral tumorigenesis, those which will be most vigorously pursued are: (i) a cell surface interaction between a viral molecule and certain H-2K or H-2D molecules serves as a trigger for events leading to "replication suppression" (cessation of virus production and virus antigen expression) which favors the emergence of tumors, or leading to induction of killer T cells, which favors the repression of tumors, and (ii) an immune response gene, presumably H-2I-linked governs the production or nonproduction of certain antiviral antibodies which may favor tumor growth (blocking antibodies) or tumor regression (cytotoxic antibodies. The methods to be employed include techniques proper to genetics, immunology and virology. The studies involve the establishment and analysis of cell lines derived from Friend virus-induced tumors of mice differing from each other only with respect to their H-2 type. The analysis of the cell lines includes studies of virus and viral antigen production and growth characteristics in vivo. We shall attempt to map the effects of H-2 precisely within this complex locus. We will study the kinetics of replication suppression, its relation to cell-surface events, and its reproducibility in culture by treatment with antibodies to viral antigens. We will analyze the various components of the immune response of syngeneic mice to these cell lines, looking for H-2 determined (Ir gene) effects with respect to different viral antigens. We also hope to determine the site(s) of integration of the viral genomes into the host chromosomes.